Clinical and Genetic Characterization of Pituitary Gigantism: an International Collaborative Study in 208 Patients

L Rostomyan, A F Daly et al. Pituitary gigantism 22:5 745–757 Research

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients

Liliya Rostomyan*, Adrian F Daly*, Patrick Petrossians, Emil Nachev1, Anurag R Lila2, Anne-Lise Lecoq3,4,5, Beatriz Lecumberri6, Giampaolo Trivellin7, Roberto Salvatori8, Andreas G Moraitis7, Ian Holdaway9, Dianne J Kranenburg - van Klaveren10, Maria Chiara Zatelli11, Nuria Palacios12, Cecile Nozieres13, Margaret Zacharin14, Tapani Ebeling15, Marja Ojaniemi15, Liudmila Rozhinskaya16, Elisa Verrua17, Marie-Lise Jaffrain-Rea18,19, Silvia Filipponi18,19, Daria Gusakova20, Vyacheslav Pronin21, Jerome Bertherat22, Zhanna Belaya16, Irena Ilovayskaya23, Mona Sahnoun-Fathallah24, Caroline Sievers25, Gunter K Stalla25, Emilie Castermans, Jean-Hubert Caberg, Ekaterina Sorkina21, Renata Simona Auriemma26, Sachin Mittal27, Maria Kareva16, Philippe A Lysy28, Philippe Emy29, Ernesto De Menis30, Catherine S Choong31, Giovanna Mantovani17, Vincent Bours, Wouter De Herder10, Thierry Brue24,32, Anne Barlier24,33, Sebastian J C M M Neggers10, Sabina Zacharieva1, Philippe Chanson3,4,5, Nalini Samir Shah2, Constantine A Stratakis7, Luciana A Naves34 and Albert Beckers

Departments of Endocrinology and Human Genetics, Centre Hospitalier Universitaire de Lie` ge, University of Lie` ge, Domaine Universitaire du Sart-Tilman, 4000 Lie` ge, Belgium

Endocrine-Related Cancer 1Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria 2Department of Endocrinology, King Edward Memorial Hospital, Mumbai, India 3Assistance Publique-Hoˆ pitaux de Paris, Hoˆ pitaux Universitaires Paris-Sud, Service d’Endocrinologie et des Maladies de la Reproduction et Centre de Re´ fe´ rence des Maladies Endocriniennes Rares de la Croissance, Le Kremlin-Biceˆ tre F-94275, France 4UMR S1185, Univ Paris-Sud, F-94276 Le Kremlin-Biceˆ tre, France 5INSERM U1185, Faculte´ de Me´ decine Paris-Sud, F-94276 Le Kremlin-Biceˆ tre, France 6Servicio de Endocrinologıá y Nutricio´ n, Hospital Universitario La Paz, Madrid, Spain 7Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics & Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA 8Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 9Department of Endocrinology, Greenlane Clinical Centre, Auckland, New Zealand 10Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands 11Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Via Savonarola 9, 44121 Ferrara, Italy 12Servicio de Endocrinologıá, Hospital Universitario Puerta De Hierro, Majadahonda, Madrid, Spain 13Service d’endocrinologie-diabe´ tologie, Centre Hospitalier Lucien Hussel, Monte´ e du Docteur Chapuis BP127, 38 209 Vienne cedex, France 14Murdoch Children’s Research Institute, Royal Children’s Hospital, University of Melbourne, Parkville, Victoria, Australia 15Departments of Internal Medicine and Pediatrics, Oulu University Hospital, University of Oulu, Oulu, Finland 16Departments of Neuroendocrinology and Bone Diseases, and Department of Endocrinology, Endocrinology Research Centre, Moscow, Russia 17Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Unit of Endocrinology and Metabolic Diseases, Department of Clinical Sciences and Community Health, University of Milan, Via F. Sforza, 35, 20122 Milan, Italy 18Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 19Neuromed IRCCS, Pozzili, Italy

http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientiﬁca Ltd. DOI: 10.1530/ERC-15-0320 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 08:12:17PM via free access Research L Rostomyan, A F Daly et al. Pituitary gigantism 22:5 746

20Andrology Department, NA Lopatkin Scientiﬁc Research Institute of Urology, Moscow, Russia 21Endocrinology Clinic, I.M. Sechenov First Moscow State Medical University, Moscow, Russia 22INSERM U1016, Institut Cochin, Universite´ Paris Descartes, Hoˆ pital Cochin, Service d’Endocrinologie, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France 23Endocrinology Department, Moscow Regional Research & Clinical Institute, Moscow, Russia 24Aix-Marseille Universite´ , CNRS, UMR7286, 13015 Marseille, France 25Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany 26Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University “Federico II”, Naples, Italy 27Department of Endocrinology, T.N. Medical College & B.Y.L. Nair Hospital, Mumbai, India 28Pediatric Endocrinology Unit, Department of Pediatrics, Clinique Universitaire Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium 29Service D’endocrinologie, CHR Orle´ ans, Orle´ ans, France 30Endocrinology, Ospedale Generale Montebelluna, Montebelluna, Italy 31Department of Paediatric Endocrinology, Princess Margaret Hospital for Children and School of Pediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia Correspondence 32Department of Endocrinology, APHM Conception, 13385 Marseille, France should be addressed 33Laboratory of Molecular Biology, APHM Conception, 13385 Marseille, France to A Beckers 34Department of Endocrinology, Faculty of Medicine, University of Brasilia, Brasilia, Brazil Email *(L Rostomyan and A F Daly contributed equally to this work) [email protected]

Abstract

Despite being a classical growth disorder, pituitary gigantism has not been studied previously Key Words in a standardized way. We performed a retrospective, multicenter, international study to " gigantism characterize a large series of pituitary gigantism patients. We included 208 patients (163 " pituitary adenoma males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity " somatotropinoma for age or final height O2 S.D. above country normal means. The median onset of rapid growth " growth hormone was 13 years and occurred significantly earlier in females than in males; pituitary adenomas " aryl hydrocarbon receptor were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were interacting protein gene R10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and " familial isolated pituitary adenoma (FIPA) invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final " X-linked acrogigantism Endocrine-Related Cancer height was greater in younger onset patients, with larger tumors and higher GH levels. Later (X-LAG) syndrome disease control was associated with a greater difference from mid-parental height (rZ0.23, PZ0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 – X-linked acrogigantism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many O cases, but no genetic etiology is seen in 50% of cases. Endocrine-Related Cancer (2015) 22, 745–757

Introduction

Interest in the extremes of height stretches back into screening activities in childhood are geared to identifying antiquity, and the occurrence of people with gigantism these cases for early investigation and intervention (Chee- has contributed to popular myths across many cultures. tham & Davies 2014). Overgrowth is less well understood Even with the recognition that many extreme cases of tall and, particularly if unaccompanied by other syndromic stature are disease manifestations, interest in gigantism has features like developmental delay, its diagnosis may be unfortunately remained focused on the visual spectacle, slower. Societal factors may contribute to this, as tall stature even today. Many forms of short stature are known and is seen a less ‘undesirable’ physical feature than short stature

(Batty et al.2009). However, increased height also carries Belgium, Brazil, Bulgaria, Canada, Denmark, India, Italy, risks in terms of disease (Lee et al.2009), and excessive final Finland, France, Germany, New Zealand, Romania, Russia, adult height carries with it distinct disadvantages, particu- Spain, the Netherlands and the United States. This study larly skeletal and orthopedic problems (Hazebroek-Kamps- was approved by the Ethics Committee of CHU de Lie`ge chreur et al.1994, Silventoinen et al.1999). Surprisingly, the (Belgian clinical trials number: B707201111968). Patients functional and psychological impacts of extreme tall stature were identified at the participating centers and both have yet to be studied in detail. historical and current follow-up data were collected; results Growth and stature are determined by highly complex of previous genetic tests were collected retrospectively, and processes involving genetic and environmental factors, other genetic analyses were also performed prospectively such as endocrine function, nutrition, vitamin status and over the course of the study. Patients consented to the psychosocial wellbeing (Tanner & O’Keeffe 1962, Mascie- collection and use of clinical data and provided informed Taylor 1991, Wood et al. 2014). Diseases causing tall consent in their local language for genetic studies. stature must be differentiated from other normal variations in height, in which underlying abnormalities Eligibility criteria are absent. Pathological tall stature can be isolated or syndromic; the latter is usually due to a chromosomal or The diagnosis of pituitary gigantism was defined as current genetic cause, such as Klinefelter syndrome, Marfan or previous evidence of abnormal, progressive and syndrome and Sotos syndrome among others (Davies & excessively rapid growth velocity for age (O97th percen- Cheetham 2014). Disorders of the growth hormone (GH) tile, which corresponds to OC2 S.D.), or a final height axis can lead to abnormal height, the most classical of OC2 S.D. above the mean for relevant population, which is pituitary gigantism, usually due to over-secretion associated with elevated GH/insulin-like growth factor 1 of GH by a pituitary adenoma occurring before epiphyseal (IGF1) and imaging evidence of a pituitary lesion. Details closure (Daughaday 1992, Eugster & Pescovitz 1999, on height sources for the countries are listed in Eugster 2000). In recent years a variety of genetic factors Supplementary Materials and methods, see section on that predispose to somatotrope adenomas or hyperplasia supplementary data given at the end of this article. have been identified. Mutations in genes such as GNAS and PRKAR1A and particularly AIP are associated with Patient disposition acromegaly and gigantism (Daly et al. 2010a, Xekouki et al. Endocrine-Related Cancer 2010, Stratakis 2015). X-linked acrogigantism (X-LAG) Patient information (demographics, medical and familial syndrome is associated with a microduplication, including history, genetics, clinical examination, laboratory investi- the GPR101 gene, on chromosome Xq26.3 and leads to gations, radiology, disease status during follow-up, treatment pituitary hyperplasia and adenomas in children and early modalities and response to therapy) were systematically onset gigantism beginning usually in the first year of life collected in each study center, recorded in the case report (Trivellin et al. 2014, Beckers et al. 2015). form and transmitted anonymized to the coordinating Due to its rarity and despite the recent emphasis on center. All patients with pituitary causes of gigantism pathophysiological causes, the clinical presentation, diagnosed at any time at the participating centers were evolution, complications and responses to treatment of valid for inclusion. Overall, 229 patients were enrolled; patients with pituitary gigantism have not been studied in 21 cases were ineligible and excluded (Klinefelter’s syndrome a large cohort. To address these issues, we conducted an (nZ5),constitutionaltallstature(nZ3), Sotos syndrome international collaborative study of the features of (nZ2), obesity (nZ2), ectopic growth hormone-releasing patients with pituitary gigantism. hormone (GHRH) secretion (nZ1) and tall stature of unknown etiology without GH axis excess (nZ8)). The final Methods study population consisted of 208 patients diagnosed with pituitary gigantism (Supplementary Figure 1,seesectionon This was a study that included patients with pituitary supplementary data given at the end of this article). gigantism due to a pituitary adenoma or hyperplasia. The study was performed between 2011 and 2013 at the Study measures Department of Endocrinology, Centre Hospitalier Universitaire de Lie`ge, Belgium, in collaboration with Height was expressed as Z-scores above the mean value 46 other international centers in Argentina, Australia, of height of the reference population. The mid-parental

height (MPH) was defined as the average of the parents’ R3 modalities. Long-term disease control criteria heights K6.5 cm for girls and C6.5 cm for boys. The (R12 months of follow-up) were shrinkage or stable size difference of the final height from MPH was used to of pituitary adenoma, the absence of clinical activity, an determine the variance from target stature. age/sex-appropriate IGF1 that was %upper limit of normal The age at disease onset was derived from existing (ULN) for the assay used at the individual clinical center patient case files and following consultation with the and a GH level !1 ng/ml at last follow-up (pegvisomant- patient and family. The age at diagnosis was assessed as the treated patients were assessed on IGF1 only). age at which a first definitive diagnosis of a pituitary gigantism was recorded in the case notes. Pituitary tumors Statistics were classified as per the local radiology reports according to the maximal diameter on magnetic resonance imaging Statistical analysis (statistical computing and graphics) or computerized tomography as microadenomas was performed using STATISTICA, version 10 (StatSoft, (!10 mm) and macroadenomas (R10 mm); the latter Tulsa, OK, USA), and R package, version 2.15.1 (R Core included giant adenomas (those measuring R40 mm). Team, Vienna, Austria). Absolute numbers and percen- Invasion of surrounding structures and extrasellar expan- tages were used to describe qualitative and categorical sion was evaluated by neuroimaging and at surgical data. Continuous data did not fit parameterized distri- intervention. butions, therefore they were represented as medians and Therapeutic modalities were assessed and details interquartile ranges (IQR) and non-parametric statistical collected; a total treatment score was calculated as the tests were used for the analysis (Spearman’s R and c2) tests sum of the use of somatostatin analogues (SSA), pegviso- for the association between variables and Mann–Whitney mant, dopamine agonists (DA), each individual surgery U and Kruskal–Wallis tests for comparison of independent and radiotherapy (each was allocated one point). The subgroups). A P-value of !0.05 was designated as the level multimodal treatment approach was considered with of statistical significance.

Table 1 Clinical characteristics of patients with pituitary gigantism

Study criteria Total group Males (nZ163) 78% Females (nZ45) 22%

Endocrine-Related Cancer Age at rapid growth onset (year)a 13 (9; 15) 13 (10; 15) 11 (3; 14) Patients who had not attained final height (%) 15.9% 13.5% 25.6% Age at which final height was attained (year) 20 (18; 22) 20 (18; 22) 18.5 (16; 23) Age at first symptoms (year)a 14 (10; 16) 14 (11; 16) 12.5 (2; 14) Age at diagnosis of PA (year)a 21 (15.5; 27) 21.5 (17; 28) 15.8 (10; 23) Aged %19 years (%)a 42.4% 37.3% 61.9% Delay from symptoms to diagnosis (year)a 5.3 (2.0; 11.0) 6.2 (3; 12) 2.5 (1.0; 6.0) Height Z-score (S.D.) 3.1 (2.5; 4.0) 3.1 (2.5; 4) 3.1 (2.6; 4.1) Age at height measurement (year) 29 (21; 37) 29 (22; 38) 28 (17; 35) Difference from MPH Absolute (cm) 20 (15; 24) 19.5 (15; 23) 21 (15; 26.3) % from MPH 11.6 (8.5; 14.8) 11.2 (8.4; 13.7) 12.9 (8.7; 16.4) Maximal dimension of PA (mm) 22 (14; 34) 21 (14; 32) 24.5 (15; 36) Macroadenoma (%) 84.3% 85.1% 81.6% Giant adenoma (%) 15% 14.6% 16.7% Extension (%) 77.2% 77% 78% Invasion (%) 54.5% 54.9% 53.3% GH level at diagnosis (ng/ml)a 35.5 (14; 83) 29 (12.3; 64) 62.3 (27.8; 95) IGF1 level at diagnosis (% ULN) 254.5 (189.5; 359.5) 250 (188; 358.5) 268 (198; 421) Prolactin co-secretion (%) 34% 31% 46.9% Multimodal treatment (%) 32.2% 32.1% 32.5% GH/IGF1 control at last follow-up (%) 45% 49% 32.5% Age when GH/IGF1 control achieved (year) 23 (17; 30.5) 23.5 (17.8; 31) 17.7 (11; 29.5) GH/IGF1 controlled %19 years (%) 36.6% 32.1% 55% GH/IGF1 controlled before final height (%) 20.8% 19.2% 26.8% Long-term control (%) 39% 42% 30%

All continuous data presented as median and IQR. PA, pituitary adenoma. Multimodal treatment: R3 separate modalities. aP-value !0.05 when compared females and males.

Results been diagnosed in 36.5% at baseline, mainly left ventri- cular hypertrophy (21%) and diastolic dysfunction (10%). Characteristics at diagnosis Females exhibited higher median GH levels at diagnosis The pituitary gigantism population consisted of 208 than males (62.3 (27.8; 95.0) vs 29 (12.3; 64.0) ng/ml, patients, the majority of whom were male (nZ163; 78%) respectively; PZ0.009), but IGF1 levels were similar (Table 1). Patients were diagnosed across a number of between genders. Co-secretion of prolactin occurred in decades: 1950s (1%), 1960s (1%), 1970s (3%), 1980s (13%), 34% overall and was more frequent in patients with invasive 1990s (20%), 2000s (42%) and current decade, 2010s (20%). macroadenomas with extrasellar extension. At diagnosis, R The median height Z-score was C3.1 (2.5; 4.0), the median 25% of patients had a deficit in 1 axis; among those aged % age at height measurement was 29 (21; 37) years, and the 19, hypopituitarism at baseline was seen in 18.3%. majority of patients (84.1%) had reached their final height at a median age of 20 (18; 22) years. The median age at the Treatment and follow-up onset of rapid growth was 13 (9; 15) years overall and was significantly younger in females than in males (11 (3; 14) vs Treatment regimens differed among centers due to the 13 (10; 15) years, respectively; PZ0.003). There was a availability of medical therapies (Fig. 1). The median period of follow-up on treatment was 10.4 years (4; 20) overall. median delay of 5.3 (2; 11) years between first symptom Initial surgery in 177 patients was associated with control in onset and pituitary adenoma diagnosis; this delay was 15%. Among 40 cases that were then re-operated, 7.5% of significantly shorter in females than males (2.5 (1; 6) vs 6.2 those were controlled. Postoperative SSA were used in 66.7% (3; 12) years, respectively; PZ0.03). Overall, 42.4% of (nZ118) of the patients and disease control was achieved in patients were aged %19 years at diagnosis and significantly 34% (nZ40). A further 26% (nZ54) of the patients received more female patients fell in this age group (PZ0.004). primary SSA treatment, but only 7% (nZ4) of these were The most frequent first clinical sign was increased controlled. Pegvisomant was used preoperatively either growth (w75% of patients), followed by acral enlargement alone (nZ1) or in combination with SSA or DA (nZ8); and facial changes (37%), headache (23%) and visual field control was achieved in four cases. Pegvisomant was defects (12%). Pubertal delay occurred in w29% of males administered after surgery with SSA and/or DA in 28 and females. patients; control was achieved in 53.5% (nZ15) of these Nine cases of pituitary apoplexy were reported at cases. A total of 63 patients were irradiated (two had primary Endocrine-Related Cancer baseline and seven patients had diffuse pituitary hyper- radiotherapy) with control in 43% (median follow-up: 168 plasia (radiological or surgical); the remainder had months (62; 235)); 56.5% of these also had received an SSA pituitary adenomas. Patients with diffuse pituitary hyper- during follow-up. The median number of treatment plasia presented in childhood/adolescence and were modalities was 2 (1; 3). Overall, disease control was achieved generally younger at first symptoms and had a higher in 45.6% of the patients. The median duration of follow-up height Z-score at diagnosis than the remainder of the post-treatment was 7 years (3; 17), and in those followed up gigantism cohort; these differences were not statistically for R12 months, disease control was achieved in 39.5% of significant. Pituitary tumors were predominantly macro- cases. There was a significant correlation between larger adenomas (84.3%), with 15% of those being ‘giant’ tumor diameter and a greater number of treatment adenomas. Extrasellar extension and invasion occurred modalities (rZ0.18, PZ0.02). Macroadenomas required in most cases (89% and 64% of macroadenomas, respect- significantly more treatment modalities than microadeno- ively). Radiological characteristics did not differ between mas (R3 modalities in 50% vs 19% respectively; PZ0.009). males and females. Median maximal tumor diameter was smaller in patients Despite the relatively young age of the patients, who were controlled (19 (11; 25) vs 27 mm (17.0; 37.5) in acromegalic features were present in almost all males uncontrolled cases; PZ0.0003). However, there was better (92%) and females (94%) at diagnosis (Supplementary control at the last follow-up in those patients with tumors Table 1, see section on supplementary data given at the end diagnosed at the age of %19 years than in older patients of this article). The median shoe sizes at diagnosis were 15.0 (58.5% vs 36.4% respectively; PZ0.02). Maximal tumor (13.0; 17.0) in males and 11.5 (10.5; 14.5) in females diameter at diagnosis was correlated with GH (but not IGF1) (European (EU) sizing, 48 (46.0; 50.0) and 42 (41.0; 45.0) in levels (rZ0.34, PZ0.002) at diagnosis. males and females respectively). Among 156 cases that had During follow-up, pituitary apoplexy occurred in nine cardiac assessments reported, cardiac disease had already patients. Hypopituitarism rose from 25% at baseline to

208 patients*

Primary medical therapy (58) 1st surgery (177) 7% (4) controlled (33) 15% (26) controlled

DA (3), SSA (37), PegV (1) SSA+DA (9), SSA +PegV (4), SSA+DA+PegV (4)

17% not currently (24) 36% not controlled currently controlled

(61) (36)

(15) (14) Secondary RadioThx (61) Secondary medical treatment (118) Re-operation (40) 43% (26) controlled** 34% (40) controlled (23) 7.5% (3) controlled (1) DA (17) SSA (37), SSA+DA (26) SSA (11) +PegV (9), SSA+PegV+DA (19)

(34) 44% not currently controlled *Two patients had primary radiotherapy (one controlled); Four recently diagnosed patients awaiting treatment; **Follow up- 168 months (62;235)

Figure 1 Schematic representation of treatments used in the management of patients with pituitary gigantism. Numbers in parentheses indicate the number of patients. RadioThx, radiotherapy; DA, dopamine agonists; SSA, somatostatin analogues; PegV, pegvisomant.

64% at the last follow-up. The proportions of patients with had attained their ﬁnal height (C4.1 S.D. (2.8; 5.7) and deﬁcits in the various pituitary axes at the last follow-up C2.9 S.D. (2.5; 3.8) respectively; PZ0.004).

Endocrine-Related Cancer were as follows: gonadal 62%, adrenal 47%, thyroid 41%, Excess GH/IGF1 secretion was controlled before the GH 10% and diabetes insipidus 8%. Among the patients end of linear growth in 20.8% of the total group; in 11 of with hypopituitarism, 92.6% had undergone surgery and these cases, hormonal control led to a normalization of 46% had received radiotherapy. In those aged %19 years the growth pattern and a height at last follow-up that was at diagnosis, hypopituitarism was present at diagnosis in !C2 S.D.(Fig. 2). Hormonal control at %19 years of age 18.3% and in 66% after treatment, with a deficiency of was associated with an earlier halting of linear growth three pituitary axes in 29% and panhypopituitarism than in those controlled after that age (PZ0.0052). in 3%. The presence of hypopituitarism at the last Overall, patients’ final height exceeded their MPH by a follow-up was significantly related to larger tumor size median difference of 20 cm (15; 24) and no gender (30 mm (20; 39) vs 15.5 mm (10; 25); PZ0.006) but not to differences were seen. duration or control of the disease. Height Z-score and the difference from MPH correlated Seven patients (3.4%) died during follow-up; causes of significantly with tumor size (rZ0.2, PZ0.03) and GH (but death were thrombosis/embolism (nZ2), hemorrhage, not IGF1) at diagnosis (rZ0.29, PZ0.0001). Height Z-scores myocardial infarction, tumor progression, accident and were also significantly greater in those who were younger suicide (nZ1 each). both at first symptoms (rZK0.3, PZ0.01) and at the start of rapid growth (rZK0.19, PZ0.01). The difference of final height from MPH depended on age when first control was Growth responses achieved (rZ0.23, PZ0.02), being significantly lower in The height of each patient expressed in Z-scores above the those with disease control aged %19 years than thereafter mean and their age at the last measurement are shown (10.9% (7.7; 13.8) vs 12.7% (9.32; 16.3) respectively; in Fig. 2. The median height Z-score at diagnosis was PZ0.044). Median excess over MPH was greater in patients higher in those who were still growing than those who with hypogonadism or pubertal delay than in those

tumor size and lower rates of invasion and extension as AIP mutation-positive cases (Fig. 4; Table 2). 9 Males stopped growing Males growing Females stopped growing 8 Females growing Discussion 7 In this study we report the clinical and genetic charac- 6 teristics of 208 patients with pituitary gigantism due to GH -score

Z 5 hypersecretion. This, the ﬁrst extensive series of patients with radiologically and hormonally proven pituitary 4 Height gigantism, provides insights into the disease proﬁle of 3 this rare disorder. Genetic or familial disease was seen in 46% of the cases tested. Of the tested cases, 29% had AIP 2 mutations or deletions. Previous studies have noted that 1 AIP mutations are associated with gigantism, either sporadic, within individual FIPA kindreds or in large 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 historical studies (Naves et al. 2007, Jennings et al. 2009, Age (years) Daly et al. 2010a, Chahal et al. 2011). This high frequency of AIP mutations among pituitary gigantism patients Figure 2 is logical, given that AIP mutations are characteristically Age and Z-score for height of patients at the last follow-up. Of the total common among children and young adults and most population of 208 patients, 57 patients had an absolute height O200 cm at the last measurement (eight are still growing) and the tallest patient was frequently lead to somatotropinomas (Stratakis et al. 2010, 247 cm. Of those who were controlled before the end of the linear growth, Tichomirowa et al. 2011). X-LAG syndrome is a recently 11 had a height at the last follow-up of !C2 S.D. (seven of these later had a described form of pituitary gigantism due to chromosome disease recurrence).

with normal gonadal status (12.8% (8.8; 16.3) vs 10.7% (8.5; 13.3) respectively; PZ0.04). Endocrine-Related Cancer Genetic studies

In the study population, 143 pituitary gigantism patients consented to genetic testing (AIP, MEN1, PRKAR1A, GNAS1, Xq26.3 duplication) and 46% had genetic causes

or inherited syndromes (Fig. 3). In total, 29% of the patients AIP+ were positive for AIP mutations. There were 28 familial 29% isolated pituitary adenoma (FIPA) patients (23 males) of whom 18 had AIP mutations. Four members of two FIPA

families had Xq26.3 microduplications and X-LAG syn- X-LAG drome, as did a further ten sporadic cases. In addition, 10% seven McCune-Albright syndrome, two familial Carney MAS Complex and one MEN1 gigantism case were observed; 5% Genetically– 54% of the patients had no genetic cause identiﬁed. 54% As compared with the AIP mutation-positive patients,

those with no detected genetic cause were significantly Carney complex 1% more likely to be female, were older at first symptoms and MEN1 1% at diagnosis (fewer cases were aged %19 years) and had a longer disease latency, with higher GH/IGF1 levels, more Figure 3 frequent multimodal therapy and poorer overall control Genetic results in the study population. Numbers for each sector show the number of patients in the subgroup and its prevalence in the total group. rates (Fig. 4; Table 2). X-LAG cases were predominantly AIPC, AIP mutation affected; Genetically –, genetically negative testing; female and significantly younger at onset but had similar MAS, McCune-Albright Syndrome; X-LAG, X-linked acrogigantism syndrome.

AB22 45 P<0.0001 P<0.0001 20 40 18 35 16 30 14 12 25 10 20 8 15

6 Age at diagnosis of 10 4 pituitary adenoma (years)

Age at onset of disease (years) 2 5 0 0 Genetically– AIP+ X-LAG Genetically– AIP+ X-LAG

CD100 Female Male P=0.44 60 90 80 50 70 40 60

% 50 30 40 20 30 20 10 Maximal tumor diameter (mm) 10 00 Genetically– AIP+ X-LAG Genetically– AIP+ X-LAG

Figure 4 Comparisons of characteristics among genetically distinct groups of intergroup difference in terms of maximal tumor diameter at diagnosis (C). pituitary gigantism patients (genetically negative, AIP-mutation positive (D) demonstrates the female and male predominance of X-LAG and AIPC (AIPC) and X-linked acrogigantism syndrome (X-LAG)) showing statistically related gigantism cases; the genetically negative group was also male distinct patterns of age at ﬁrst symptoms (A), age at diagnosis (B) and no predominant although less markedly so than the AIPC group.

Endocrine-Related Cancer Xq26.3 microduplications (Trivellin et al. 2014, Beckers between males and females at the end of puberty and et al. 2015) and constituted 10% of the genetically studied push more males than females into the gigantism height cases in the current study. X-LAG syndrome has a range. As AIP mutation-related adenomas are usually particularly early age at onset, can present sporadically or large, concomitant impingement on normal pituitary as FIPA and predominantly affects females. We found no tissue could lead to hypogonadism, thereby further microduplicationonXq26.3inanycasediagnosed prolonging the time to ﬁnal epiphyseal closure in males. aged O5 years in our series, whereas the youngest AIP Among patients without AIP mutations, the gender balance positive patient was 8 years old at diagnosis. Other genetic was heterogeneous: X-LAG syndrome cases are mainly causes occurred less frequently; McCune-Albright female (Trivellin et al.2014, Beckers et al. 2015), whereas Syndrome (MAS), Carney complex and MEN1 comprised cases that were negative on genetic testing were predo- 7% of gigantism overall. Although pituitary gigantism can minantly male but less markedly so than the AIP-mutated occur in both genders, it predominantly affects males group. The genetically negative group comprised more than (78%). This is likely due to male predominance among half of all cases studied. The clinical phenotype of patients AIP-mutated gigantism cases, as we reported previously in with AIP mutations or X-LAG syndrome has shown to be acromegaly (Daly et al. 2010b). This gender imbalance aggressive (Daly et al.2010a, Beckers et al. 2015). In this study may have a number of causes, including unknown we noted that genetically unexplained pituitary gigantism genetic factors. Likely contributors to the imbalance patients are even more aggressive (e.g., invasion, hormone include the typical onset of AIP mutation-related somato- levels, lower control rates) than AIP mutation cases. tropinomas during puberty when GH excess coincides with This group may be a priority for further genomic pathophy- the longer period of prepubertal growth and the greater siologic studies. pubertal peak growth velocity in males (Rogol et al.2002). An important question regarding pituitary gigantism is This could serve to augment the usual height difference whether earlier diagnosis and control of GH/IGF1 secretion

Table 2 Comparisons of characteristics between X-linked acrogigantism (X-LAG) syndrome group, AIP mutation positive (AIPmut) patients and genetically negative patients

Group I Group II Group III X-LAG syndrome AIP mut Genetically negative Study criteria nZ14 nZ42 nZ77 P1 (I vs II) P2 (I vs III) P3 (II vs III)

Gender (% of males) 29% 95% 78% 0.002 0.01 0.01 FIPA (number of 4/2 18/16 5/5 patients/number of families) Age at rapid growth onset 1.5 (1; 2) 13 (9; 15) 14 (11; 15) !0.0001 !0.0001 0.09 (year) Patients who had not reached 76.9% 12.5% 12.2% 0.005 0.0001 0.8 final height (%) Age at which final height was 23.5 (18; 29) 19 (18; 21) 20 (18; 24) 0.6 0.6 0.16 attained (year) Height Z-score (S.D.) C4.82 (C2.8; C6.1) C3.01 (C2.5; C4.1) C2.99 (C2.4; C4.0) 0.009 0.007 0.9 Age at height measurement 5 (3; 7) 26.5 (19; 33.5) 29 (24.8; 36.5) !0.0001 !0.0001 0.11 (year) Difference from MPH Absolute (cm) 10.9 (9.4; 12.4) 18.9 (16.2; 26) 21.5 (14; 24.5) 0.06 0.1 0.63 Relative (%) 6.52 (5.5; 7.5) 10.9 (8.9; 15.4) 12.7 (8.3; 16.2) 0.06 0.1 0.5 Age at first symptoms (year) 1.5 (1; 2) 13.3 (9; 16) 15.0 (13; 16) !0.0001 !0.0001 0.04 Age at diagnosis PA (year) 3 (2.6; 3.7) 16.8 (14.0; 20.0) 24.0 (19.0; 29.5) !0.0001 !0.0001 !0.0001 %19 years of age (%) 100% 71.4% 28.6% !0.0001 Delay from symptoms to 1.6 (1; 2.25) 3 (1; 6) 8 (4; 13) 0.06 !0.0001 0.0006 diagnosis (year) Macroadenoma (%) 76.9% 90.2% 92% 0.06 0.08 0.7 Giant (R40 mm) adenoma 0.0% 10.8% 22% 0.07 (as a % of macroadenomas) Extension (%) 50.0% 77.8% 88.4% 0.02 0.001 0.07 Invasion (%) 30.0% 58.1% 66.7% 0.04 0.01 0.2 Maximal dimension of PA (mm) 18 (10; 27) 25 (14; 32) 24 (17; 37.5) 0.3 0.2 0.65 GH levels at diagnosis (ng/ml) 102 (58.5; 121) 23 (14.5; 50) 43 (21.6; 88.5) 0.01 0.09 0.05 IGF1 levels at diagnosis (% ULN) 385 (285; 463) 199.5 (116.8; 282.7) 285 (205; 403) 0.003 0.2 0.001 Prolactin co-secretion (%) 82.0% 33.3% 41% 0.02 0.01 0.4

Endocrine-Related Cancer Multimodal treatment 46.0% 23.8% 42.7% 0.03 0.6 0.04 approach (%) GH/IGF1 control at last 58.0% 61.0% 43.0% 0.7 0.02 0.03 follow-up (%) Age when ﬁrst control 8.0 (4; 13) 17.3 (15; 20) 27 (18; 37) 0.006 0.0005 !0.0001 achieved (year) GH/IGF1 control %19 years (%) 85.7% 72.7% 22.7% 0.0001 GH/IGF1 control before ﬁnal 54.5% 48.6% 10.9% 0.3 !0.0001 !0.0001 height (%) Long-term control 41.7% 55.3% 38.4% 0.05 0.1 0.08 (O12 months) (%) Follow-up period on 3 (0.9; 8) 10.3 (4; 20) 7 (3; 13.5) 0.04 0.5 0.07 treatment (year) Hypopituitarism at 75% 73% 66% 0.9 0.7 0.4 follow-up (%)

All continuous data are shown as median and IQR. FIPA, familial isolated pituitary adenomas; PA, pituitary adenoma; MPH, mid-parental height; ULN, upper limit of normal range.

can influence final height. As this study included patients age at which linear growth ceased was 23 years, which is with gigantism diagnosed at any time during their growth later than in the general population – 20 years (Deaton (not only on final adult height OC2 S.D.), we were able to 2007). This delay permitted a longer period of growth address whether early recognition could limit excessive before epiphyseal closure, a factor that was exacerbated in linear growth. In the group overall, the height at last those with concomitant hypogonadism who had a greater follow-up was clearly in excess of MPH (11.6%; absolute final height. We found that a greater final height Z-score difference, 20 cm) in both males and females. The median was determined by earlier age of onset, larger tumor size

and greater GH excess. Moreover, these three features were Despite the young age at disease onset, pituitary interconnected, with younger patients developing larger adenomas were already large and most had extension tumors and higher GH secretion. Importantly, the age at and invasion at diagnosis. Elevated levels of GH and IGF1 which GH control was achieved had an important effect on (with prolactin co-secretion in one-third of cases) were final height. When control was achieved during the period seen at diagnosis and underpin the early and profound of usual linear growth (%19 years), the final height was overgrowth seen among pituitary gigantism sufferers. lower, with a decrease in the difference between MPH and Patients required multimodal treatment, with repeated final height. These findings strongly suggest that an earlier surgeries and frequent use of radiotherapy. As the study diagnosis and a more rapid achievement of hormonal was international and retrospective, not all modalities control can help reduce final height in pituitary gigantism were uniformly available in all countries, particularly patients. The delay between first symptoms of increased medical therapies like pegvisomant and SSA. Previous growth being noticed for the first time and the diagnosis of reports of individual cases or small series of pituitary a pituitary adenoma relies on a number of factors. Not only gigantism have noted challenging disease control that is good awareness of the clinical features of excessive required pegvisomant (Rix et al. 2005, Goldenberg et al. growth (including accompanying signs/symptoms) 2008). More uniform early recourse to medical therapies in important in the general population but also the urgency patients not controlled by surgery alone could theoreti- of seeking and obtaining both general and specialized cally improve the poor responses seen in the current medical input depends on the patients and families and the cohort. However, certain genetic forms of gigantism, such attitude and efficiency of the health system. Access to as AIP mutations and X-LAG syndrome, are poorly expert diagnostics and treatment is not uniform, and responsive to traditional SSA, further complicating the particularly in economically disadvantaged regions, such management (Daly et al. 2010b, Beckers et al. 2015). access may be extremely difficult to obtain. Although these Radiotherapy has a relatively slow onset of effect and may representsignificantchallenges,thisstudyprovides not be sufficient alone following failed surgery, as in the scientific evidence to support improvements in disease setting of pituitary gigantism in which the window to awareness and to improve the efficiency of current provide effective therapy and to restrain overgrowth is diagnostic and treatment networks. quite narrow. Given these challenges, it would appear In three-quarters of the cases abnormal growth was ideal that patients with suspected pituitary gigantism be the first sign/symptom reported, and it was generally referred to experienced centers with available multimodal Endocrine-Related Cancer established by late prepubertal childhood or early adoles- therapy as soon as possible to improve chances of earlier cence (median 13 years). We found that signs/symptoms effective disease control. were noted significantly earlier in females than in males, The clinical presentation included many typical disease which led to an earlier diagnosis and shorter latency features of adult acromegaly despite the relatively young period before diagnosis. A number of factors may have age of the patients (Supplementary Table 1). The range of contributed to this earlier diagnosis. Disease onset signs/symptoms was mainly influenced by the duration of overlapped with the earlier pubertal growth spurt in GH/IGF1 hypersecretion and the delay in diagnosis. These females. The superposition of abnormal acromegaly included glucose metabolism disorders, arterial hyperten- symptoms on top of accelerated vertical growth may sion and heart disease, which are more typical of an older have led to patients seeking medical attention earlier. In age group. Taking into account the poor hormonal control addition, tall stature even in healthy girls has long been rate, it was not surprising that clinical symptom rates were viewed as less socially desirable (Lee & Howell 2006), not greatly ameliorated by surgery or on medical treatment possibly contributing to an earlier recourse to medical (Supplementary Table 1). Moreover, hypopituitarism was investigation by parents and doctors. However, despite the diagnosed frequently in our cohort – probably due to high shorter latency period in females, the difference between prevalence of macroadenomas – and rose from 25% of final height and MPH did not differ between males and patients at baseline to 64% at the last follow-up due to females. This was probably due to the similar duration cumulative effects of treatment (i.e., surgery and radio- between the time of diagnosis and the time of hormonal therapy). Given the young age of disease-associated control in the two gender groups. This highlights that comorbidities, relatively low control of GH/IGF1 and the earlier recognition and diagnosis needs to be accompanied high rate of hypopituitarism, pituitary gigantism patients by rapid therapeutic intervention to control GH/IGF1 to have significant morbidity. The impact of this morbidity on influence final height. the lifespan as compared with what is established in adult

acromegaly is unknown (Biermasz 2014). In our group, small subset of the larger study group. Although this is the seven patients died, all relatively young, but specific studies most extensive genetic study of patients with pituitary are required to better assess the effects of disease burden on gigantism to date, only half of the patients consented to mortality. In addition, the impact of the often dramatic and underwent genetic testing; the final proportions of physical overgrowth on quality of life in pituitary gigantism different genetic causes (and patients with unknown patients should be addressed. causes) could therefore vary from those we report here. Height is highly variable across human populations Pituitary gigantism patients are predominantly males due to a variety of factors, including complex genetic diagnosed at a young age with macroadenomas, but influences (Silventoinen 2003, Wood et al. 2014). In females have their first symptoms and are diagnosed addition, secular trends in anthropomorphic measures, earlier than males. AIP mutations/deletions and X-LAG including height, in national or regional sub-populations syndrome account for about 40% of the patients tested. can lead to rapid changes over a few generations due to However, a genetic cause remains to be found in more factors like improved nutrition (Hesse et al.2003, than half of the pituitary gigantism patients and these Marques-Vidal et al. 2008, Jordan et al. 2012, Avila et al. patients had aggressive disease features. Final height in 2013). For this reason, the diagnosis of abnormal height gigantism was determined by an earlier age of onset, larger must be made based on appropriate population norms, tumor size and greater GH excess; control of GH excess at which ideally are country specific and regularly updated. a younger age led to a decreased final height. Treatment in We chose such normal datasets for the current study, patients with pituitary gigantism was complex and multi- which allowed us to classify patients with gigantism modal therapy was frequently needed. Pituitary gigantism according to Z-scores for height based on their own is a challenging condition, and improved management to country of origin. permit rapid diagnosis and treatment would likely be This is the first study to describe the clinical, genetic aided by greater general awareness of the condition, its and therapeutic features of pituitary gigantism in a large genetic pathophysiology and the vital role of multi- international cohort. However, there are some limitations. disciplinary surgical and medical teams. This was an analysis conducted among patients with variable disease duration and treatment history, which could impact analyses of disease control. Changes in the Supplementary data availability of modalities across time and across geo- This is linked to the online version of the paper at http://dx.doi.org/10.1530/ Endocrine-Related Cancer graphic regions are an unavoidable issue in studies of ERC-15-0320. this type and must be borne in mind. The methodology of the study was based on definitive measures to a large extent to make the analyses and conclusions more robust. Declaration of interest The authors declare that there is no conflict of interest that could be However, certain aspects, such as the age at the onset of perceived as prejudicing the impartiality of the research reported. rapid growth, may suffer from imperfect recall. Similarly, the multicenter nature of the study has implications for hormonal and radiological assessments due to hetero- Funding geneity of testing kits and normal ranges and neuroradio- This study was supported by an educational grant from the JABBS logical equipment and results. In such a rare condition, it Foundation (UK Charity Number: 1128402) and from the Fonds d’Investisse- ment de Recherche Scientifique of the Centre Hospitalier Universitaire de is not feasible for an academic (i.e., noncommercial) study Lie` ge, to A Beckers. This study is based in part on confidential data to recruit large numbers of patients at the same disease provided by Eurostat, the statistical office of the European Union: stage and receive the same diagnostic and therapeutic European Health Interview Survey (EHIS) 1 microdata. The responsibility workup measured centrally in the same laboratory and by for all conclusions drawn from the data lies entirely with the authors. the same neuroradiologists. We recognize the important variability in hormonal measurement in the GH/IGF1 axis depending on standards and methods used, and the Acknowledgements We would like to thank the following for contributing individual patient variability of normal values over time and among details: Daniel L Metzger, Hamilton Rau´ l Cassinelli, Satinath Mukhopadhyay, laboratories always requires caution (Clemmons 2011). Natalia Strebkova, Monica Tome Garcia, Jens Otto Lunde Jorgensen, Jacob As a follow-up study, we will examine the pituitary tumor Dal, Annamaria Colao, Ismene Bilbao, Jose Ignacio Labarta Aizpun, Klaus Von Werder, Ann McCormack, Nadia Mazerkina, Dominique Maiter, France characteristics of gigantism patients using the same Devuyst, Marie-Christine Vantyghem, Alexander Dreval, Simona Juliette neuroradiological methods and interpretation, albeit in a Mogos, Diego Ferone, Elena Nazzari, Vincent Rohmer, Patrice Rodien,

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Received in ﬁnal form 14 July 2015 Accepted 16 July 2015 Made available online as an Accepted Preprint 17 July 2015 Endocrine-Related Cancer